Use of 2-phenylene diamine derivatives for the treatment of infections

Abstract

The invention relates to the use of compounds of formula (I), wherein n=0-3; R 1 , R 2 =H, alkyl, aryl, heteroaryl, acyl; R 3 =H, halogen, alkyl, aryl, heteroaryl, arylalkyl, acyl, CN, NO 2 , R 4 —X—; R 4 =H, alkyl, aryl, heteroaryl, aralkyl, acyl; X=NH, O, S, SO 2 , NHSO 2 , OSO 2 , and A, B, C=organic groups. The inventive compounds are used for the prophylaxis and the therapeutic treatment of infectious processes, especially of infectious processes caused by parasites. The invention further relates to medicaments that contain the inventive compounds.

1 . Use of at least one 2-phenylene diamine derivative of general formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 n=0-3;  
 R 1 , R 2 =H, C 1-26 -alkyl, aryl, heteroaryl, C 1-26 -acyl;  
 R 3 =H, halogen, C 1-26 -alky, aryl, heteroaryl, ar-C 1-26 -alkyl, C 1-26 -acyl, CN, NO 2 , R 4 —X—;  
 with R 4 =H, C 1-26 -alkyl, aryl, heteroaryl, ar-C 1-26 -alkyl, C 1-26 -acyl; 
 X=NH, O, S, SO 2 , NHSO 2 , OSO 2 ,  
 
 A=CH 2 , CHR 5 , CR 5 R 6 , CO, CS, CONR 4 , CSNR 4 , SO 2 , PO 2 ,  
 R 5 , R 6 =independently of each other C 1-26 -alkyl, aryl, heteroaryl, ar-C 1-26 -alkyl, CN, NO 2 , COR 7 ,  
 R 7 =H, C 1-26 -alkyl, aryl, ar-C 1-26 -alkyl, C 1-26 -alkoxy, aryloxy, ar-C 1-26 -alkoxy, NR 8 R 9 ,  
 R 8 , R 9 =independently of each other H, C 1-26 -alkyl, aryl, ar-C 1-26 -alkyl, heteroaryl,  
 B=C 1-26 -alkyl, aryl, heteroaryl, arylcarbonyl, saturated heterocycles, substituted alkyl having 1-4 chain members, wherein the substituents may be Cl-g-alkyl, aryl, heteroaryl, halogen, ═O, OH, NH 2 , NH—CO—R 10 , NH—SO 2 —R 10 , COOR 11 , CO—NR 12 R 13 , CS—NR 14 R 15 , SO 2 OR 16 , SO 2 NR 17 R 18 , NH—CO—OR 19 , NH—CO—NR 2 OR 21 , NHCSNR 22 R 23 , R 10 -R 23 =independently of each other H, C 1-26 -alkyl, aryl, ar-C 1-26 -alkyl, heteroaryl,  
 D=H, C 1-26 -alkyl, aryl, heteroaryl, ar-C 1-26 -alkyl, —Y—R 24 , halogen, NO 2 , CN, NH—CO—R 25 , NH—SO 2 —R 26 , NH—CO—OR 27 , NH—CO—NR 28 R 29 , NH—CS—NR 3 OR 31 ,  
 Y=O, NH, S, CO, CS, SO 2 , COO, CONR 31 , CSNR 32 , SO 2 NR 33 ,  
 R 24 -R 33 =independently of each other H, C 1-26 -alkyl, aryl, heteroaryl, ar-C 1-26 -alkyl, and  
 Y=a group selected from  
                     
 wherein  
 Z=O, S or two hydrogen atoms,  
 R 34 =H, C 1-26 -alkyl, aryl, ar-C 1-26 -alkyl, COOR 37 , arylsulfonyl,  
 R 35 =H, C 1-26 -acyl, COOR 38 ,  
 R 36 =independently of each other H, C 1-26 -alkyl,  
 R 37 , R 38 =independently of each other C 1-26 -alkyl, aryl, ar-C 1-26 -alkyl, or  
                     
 wherein  
 Z=O, S or two hydrogen atoms,  
 R 34 =H, C 1-26 -alkyl, aryl, ar-C 1-26 -alkyl, COOR 37 , arylsulfonyl,  
 R 35 =H, C 1-26 -acyl, COOR 38    
 R 37 , R 38 =independently of each other C 1-26 -alkyl, aryl, ar-C 1-26 -alkyl, or  
                     
 wherein  
 Z=O, S or two hydrogen atoms,  
 m=0-3  
 R 34 =H, C 1-26 -alkyl, aryl, ar-C 1-26 -alkyl, COOR 37 , aryl sulfonyl,  
 R 37 =C 1-26 -alkyl, aryl, ar-C 1-26 -alkyl, or  
                     
 wherein  
 F=CH 2 , CO, CS, SO 2 ,  
 G=COOR 39 , CONHOH, CONR 40 R 41 , CSNR 42 R 43 , C 1-26 -alkyl- or alkyl substituted by aryl and having 1-3 chain members or alkyl having 1-3 chain members, which supports a substituent at the terminal C-atom the substituent selected from COOR 44 , CONHOH, CONR 45 R 46 , CSNR 47 R 48 , SR 49 , SOR 50 , SO 2 R 51 , SO 2 NR 52 R 53 , PO(OR 54 )OR 55 , PO(OR 56 )NR 57   2 , OSO 2 R 58 , O(PO)OR 59 , NHSO 2 R 60 , NHPO 2 R 61 , NHCOR 62 , NHCSR 63 , NHCONR 64 R 65 , NHCSNR 66 R 67 , —S(NH) 2 —R 68  or NH(C═NR 70 )NHR 69 , furthermore aryl or heteroaryl,  
 R 39 -R 69 =independently of each other H, C 1-26 -alkyl, aryl,  
 R 70 =CONH 2 , SO 2 NH 2 , or is  
                     
 wherein 
 H=CH 2 , CO, CS, CHR 71 , CR 72 R 73 , SO 2 , SO, PO 2 ,  
 I=C 1-26 -alkylene, C 1-26 -alkylene, in which one methylene group is replaced by O, S, or NR 77 , or C 2-26 -alaenylene, these alkylene or alkenylene radicals being unsubstituted or substituted by aryl, heteroaryl, halogen, OH, CN, C 1-9 -alkyloxy, aryloxy, COOR 74 , CONR 75 R 76 , NR 77 R 78 , NH(C═NR 70 )NHR 69 , SR 79 , SO 2 R 80 ; furthermore C 3-8 -cycloalkylene, unsubstituted or substituted by aryl, heteroaryl, halogen, OH, CN, C 1-9 -alkyloxy, aryloxy, COOR 74 , CONR 75 R 76 , NR 77 R 78 , SR 79 , SO 2 R 80 ; C 3-8 -cycloalkylene, wherein the alkylene chain is interrupted by O, S or NR 77 , arylene, unsubstituted or substituted by aryl, heteroaryl, halogen, OH, CN, C 1-26 -alkoxy, aryloxy, COOR 74 , CONR 75 R 76 , NR 77 R 78 , SR 79 , SOR 80 ,  
 R 71 -R 80 =independently of each other H, C 1-26 -alkyl, aryl, ar-C 1-26 -alkyl, heteroaryl,  
 J=a bonding or CO, COO, CONR 81 , CS, CSNR 82 , SO 2 , S(NH) 2 , SO(NH), SO 2 O, SO 2 NR 83 , PO(OR 84 ), PO(OR 85 )NR 86 , NR 87 CO, NR 88 CS, NR 89 SO 2 , OSO 2 , NR 90 PO(OR 84 ), OPO(OR 91 ), PO(OR 84 )O, NR 92 CONR 93 , NR 94 CSNR 95 , NR 96 SO 2 NR 97 , NR 98 C(NR 99 )NR 100 ,  
 R 81 -R 100 =independently of each other H, C 1-26 -alkyl, aryl, ar-C 1-26 -alkyl, heteroaryl,  
 R 99 =H, C 1-26 -alkyl, aryl, ar-C 1-26 -alkyl, heteroaryl, CONR 101 R 102 , CSNR 103 R 104 , SO 2 NR 105 R 106    
 R 101 -R 106 =independently of each other H, C 1-26 -alkyl, aryl, ar-C 1-26 -alkyl, heteroaryl,  
 K=branched or unbranched C 11-23 -alkyl, branched or unbranched C 11-23 -alkenyl being unsubstituted or substituted by aryl or heteroaryl, C 11-23 -alkinyl, aryl, heteroaryl, ar-C 1-26 -alkyl, wherein aryl, heteroaryl and ar-C 1-26 -alkyl are substituted by further aryl-, heteroaryl- and/or ar-C 1-26 -alkyl radicals,  
 or one of its salts for the therapeutic and prophylactic treatment of infections.  
 
 
     
     
         2 . Use according to  claim 1 , characterized in that the following is valid for the compounds of formula (I) gilt: 
 n=0-3,    R 1 , R 2 and R 3 =H,    A=CO, SO 2 ,    B=phenyl, benzyl, phenethyl, 4-chlorophenylmethyl, 4-bromophenylmethyl, 4-nitrophenylmethyl, 4-trifluoromethylphenylmethyl, 4-methylphenylmethyl, 1-(4-methyl-1-piperazinyl)-1-(4-trifluoromethylphenyl)methyl, 1-(4-methyl-1-piperazinyl)-1-phenylmethyl, 4-phenylphenyl-methyl, 1-naphthylmethyl, 2-naphthylmethyl, benzoyl, 2,4,4-trimethylpentyl, 2-carboxyethyl, 3-carboxypropyl,    D=benzoyl,    Y=   a radical of formula (II),    wherein    Z=O,    R 34 =H, benzyloxycarbonyl, trityl,    R 35 =H, benzyloxycarbonyl, tert.-butyloxycarbonyl,    R 36 =H.    or a radical of formula (III),    wherein    Z=O,    R 34 =H, tosyl, benzyl, 4-nitrobenzyl, 4-cyanobenzyl, benzyloxycarbonyl,    R 35 =H, benzyloxycarbonyl, tert.-butyloxycarbonyl,    or a radical of formula (IV),    wherein    Z=O,    m=0-3,    R 34 =H, tosyl, benzyl, 4-nitrobenzyl, 4-cyanobenzyl, benzyloxycarbonyl,    or a radical of formula (V),    wherein    F=CO, CH 2 , SO 2 ,    G=COOH, COOMe, CONHOH, CH 2 —COOH, CH 2 COOMe, CH 2 CONHOH, CH 2 CONH—(C 14 -C 20 )-alkyl, CH 2 CH 2 COOH, CH 2 CH 2 COOMe, CH 2 CH 2 CONHOH, CH 2 CH 2 CONH—(C 14-C   20 )-alkyl, CH 2 CH 2 CH 2 COOH, CH 2 CH 2 CH 2 COOMe, CH 2 CH 2 CH 2 CONHOH, CH 2 CH 2 CH 2 CONH—(C 14 -C 20 )-alkyl, phenyl, naphthyl, pyrridyl, fluorenyl, anthracenyl,    or a radical of formula (VI),    wherein    H=CO, SO 2 ,    I=methylene, 1,2-ethylene, 1,3-trimethylene, 1,4-tetramethylene, —CH 2 —S—CH 2 —, —CH 2 —O—CH 2 —, —CH 2 —NH—CH 2 —, 1,2-ethenylene, 1,1-ethylene, prop-1-en-1,3-ylene, prop-2-en-1,3-ylene, benzylene, 2-phenyl-1,1-ethylene, carboxymethylene, amino carbonyl methylene, 2-Carboxy-1,1-ethylene, 2-aminocarbonyl-1,1-ethylene, 3-carboxy-1,1-propylene, 3-aminocarbonyl-1,1-propylene, 2-methyl-1,1-propylene, 3-methyl-1,1-butylene, 2-methyl-1,1-butylene, pyrrolidine connected via N1 and C2, 1,2-phenylene, 1,3-phenylene, 1,2-naphthylene, 1,3-naphthylene, 1,1-cyclopentylene, 1,1-cyclohexylene, 1,2-cyclohexylene,    J=a bonding, CO, CS, SO 2 , PO(OMe), PO(OH), CONH, CSNH, SO 2 NH, PO(OH)O, PO(OH)NH, PO(OMe)O, PO(OMe)NH,    K=(C 13 -C 19 )-alkyl, (C 13 -C 19 )-alkenyl, 4-benzyloxystyryl, 4-styrylstyryl, 4-phenylstyryl, 4-cyanostyryl, 4-nitrostyryl, phenyl, 4-biphenylyl, 4-nitrophenyl, 4-cyanophenyl, 4-methylsulfonylphenyl, 4-methoxyphenyl, 4-bromophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-Formylphenyl, 4-methoxycarbonylphenyl, 4-(1,1-dicyano-2-vinyl)phenyl, 4-aminophenyl, 4-ethylphenyl, 4-Isopropylphenyl, 4-tert.-butylphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-benzyloxyphenyl, 3,4-bis-(benzyloxy)phenyl 3-phenoxyphenyl, 4-styrylphenyl 1-naphthyl, 2-naphthyl, 2-fluorenyl, 2-(2-phenylthiazol-4-yl), 5-(4-nitrophenyl)thiazo-4-yl) 5-(4-nitrophenyl)-furan-2-yl), 5-(3-nitrophenyl)furan-2-yl), 5-(2-nitrophenyl)furan-2-yl), 5-(4-bromophenyl)furan-2-yl), 5-(4-chlorophenyl)furan-2-yl), 5-(3-trifluoromethylphenyl)-furan-2-yl), 5-(4-trifluoromethylphenyl)furan-2-yl), 5-(2-chloro-3-trifluoromethylphenyl)-furan-2-yl) 3,4-methylenedioxyphenyl, 1-acetylindol-3-yl, 4′-nitrobiphenylyl, 5-(4-bromophenyl)thiophen-2-yl), 5-(4-methylphenyl)furan-2-yl), 5-(4-methoxyphenyl)furan-2-yl), 5-bromothiophen-2-yl, 5-bromofuran-2-yl, 4-pyridyl, 3-pyridyl, 2-pyridyl, Chinolin-2-yl, 1-naphthylvinyl, 2-naphthylvinyl, 2-fluorenyl-vinyl, 2-(2-phenylthiazol-4-yl)vinyl, 2-[5-(4-nitrophenyl)furan-2-yl)vinyl, 2-[5-(4-acetoxy-methylphenyl)furan-2-yl)vinyl, 2-[5-(3-trifluoromethylphenyl)furan-2-yl)vinyl, 4-benzyloxy-styryl, 3,4-dibenzyloxystyryl, 3-methoxy-4-(4-nitrobenzyloxy)styryl, 2-methylindol-3-ylvinyl, 1acetylindol-3-ylvinyl, 3,4-methylenedioxystyryl, 4-(1,1 dicyano-2-vinyl)styryl and the salts thereof.    
     
     
         3 . Use according to  claim 1 , characterized in that the following is valid for the compounds of formula (I): 
 n=0-3,    R 1 , R 2 =H    R 3 H,    A=CO, SO 2 ,    B=phenyl, benzyl, phenethyl, 4-chlorophenylmethyl, 4-methylphenylmethyl, 1-(4-methyl-1-piperazinyl)-1-(4-trifluoromethylphenyl)methyl, 1-(4-methyl-1-piperazinyl)-1-phenylmethyl, 4-bromophenylmethyl, 4-nitrophenylmethyl, 4-trifluoromethylphenylmethyl, 4-phenylphenyl-methyl, 1-naphthylmethyl, 2-naphthylmethyl, benzoyl, 2,4,4-trimethylpentyl, 2-Carboxyethyl, 3-Carboxypropyl,    D=benzoyl,    Y=   a radical of formula (IV)    wherein    Z=O,    m=0-3,    R 34 =H, benzyl, 4-nitrobenzyl, 4-cyanobenzyl,    or a radical of formula (V)    wherein    F=CO, CH 2  SO 2 ,    G=CH 2 CH 2 CONR—(C 14 -C 18 )-alkyl, CH 2 CH 2 CH 2 CONH—(C 14 -C 18 )-alkyl, phenyl, naphthyl, pyridyl, fluorenyl, anthracenyl    or a radical of formula (VI)    H=CO,    I=methylene, 1,2-ethylene, 1,3-trimethylene, 1,4-tetramethylene, —CH 2 —S—CH 2 —, —CH 2 —O—CH 2 —, —CH 2 —NH—CH 2 —, 1,2-ethenylene, 1,1-ethylene, prop-1-en-1,3-ylene, prop-2-en-1,3-ylene, benzylene, 2-phenyl-1,1-ethylene, 2-methyl-1,1-propylene, 3-methyl-1,1-butylene, 2-methyl-1,1-butylene, pyrrolidine connected via N1 and C2,    J=PO(OMe), PO(OH), CONH, CSNH, SO 2 NH, PO(OH)O, PO(OH)NH, PO(OMe)O, PO(OMe)NH,    K=(C 13 -C 19 )-alkyl, (C 13 -C 19 )-alkenyl, 4-benzyloxystyryl, 4-phenylstyryl, 4-cyanostyryl, 4-nitrostyryl, phenyl, 4-biphenylyl, 4-nitrophenyl, 4-cyanophenyl, 4-methoxyphenyl, 1-naphthylvinyl, 2-naphthylvinyl, 2-fluorenylvinyl, 2-(2-phenylthiazol-4-yl)vinyl, 2-[5-(4-nitrophenyl)furan-2-yl)vinyl, 2-[5-(4-acetoxymethylphenyl)furan-2-yl)vinyl, 2-[5-(3-trifluoromethylphenyl)furan-2-yl)vinyl, 3,4-dibenzyloxystyryl, 3-methoxy-4-(4-nitrobenzyloxy)styryl, 3,4-methylenedioxystyryl, 4-(1,1 dicyano-2-vinyl)styryl and the salts thereof.    
     
     
         4 . Use according to one of  claims 1  to  4 , characterized in that A represents CO and B represents benzyl or 4-methylphenylmethyl and D represents benzoyl.  
     
     
         5 . Use according to  claim 4 , characterized in that die compounds of formula (I) is selected from the group consisting of  
       
         
           
           
               
               
           
         
       
     
     
         6 . Use according to  claim 1 , characterized in that die compounds of formula (I) selected from the group consisting of N-[3-[3-benzoyl-4-[2-(4-methylphenyl)-acetyl]amino]-phenylamino]-4-phenyl cinnamic acid amide and N-[2-[3-benzoyl-4-[[2-(4-methylphenyl)acetyl]-amino]phenyl]-4-benzyloxy cinnamic acid amide.  
     
     
         7 . Use according to one of  claims 1  to  6  for the prophylactics and treatment of infections caused by parasites, especially unicellular parasites, namely pathogens of malaria, the sleeping sickness, the Chagas' disease, the toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pnemacystosis, balantidiosis, cryptosporidiosis, sarcocystosis, acanthamebiasis, naegleriasis, coccidiosis, giardiasis and lambliosis.  
     
     
         8 . Pharmaceutical preparation for the therapeutic and prophylactic treatment of infectious processes, characterized in that the preparation contains an effective amount of at least one compound according to one of  claims 1  to  6  together with a pharmaceutically acceptable carrier.  
     
     
         9 . Pharmaceutical preparation according to  claim 8 , characterized in that the preparation contains a further pharmaceutical active agent.